Restless Legs Syndrome (RLS) is a sensorimotor disorder that strongly affects, primarily, disrupts sleep [1, 2]. Symptoms include throbbing, pulling, creeping, or other unpleasant sensations in the legs and an uncontrollable urge to move them. These symptoms occur in a circadian fashion and primarily at night, and the sensations range in severity from uncomfortable to irritating to painful [3, 4]. Epidemiologic surveys report a prevalence of RLS between 2.5-10% of the overall population [5-8], making it, with more than 3 million cases in the US alone, the most common movement disorder, and one of the most common sleep disorders.
Several genome-wide association studies have identified genetic markers that are highly expressed in RLS patients [5, 9-13], however, the function of these genes in the nervous system and their contribution to RLS remains unclear. The current primary treatment paradigm for RLS generally focuses on levodopa and dopamine (DA) receptor agonists that target the Gi-coupled inhibitory DA receptors (in particular the subtypes D3R and D2R) [3, 14-18].
Many RLS patients respond robustly to the DA receptor agonists, and D3R agonists can act as early as on the first day of treatment [19]. However, long-term therapy often leads to augmentation and a switch of the initially beneficial actions into adverse effects [20-24]. First described in the therapy of RLS in 1996 [25], augmentation is characterized by an earlier onset of symptoms in the afternoon, a shorter latency to onset of symptoms when at rest, an expansion of symptoms to the upper limbs and the trunk, an overall increase in the intensity of symptoms, including paresthesia [26], and a shorter-lasting therapeutical effect of the medication [27]. Thus DA agonists appear to have a limited period of clinical utility for many patients, and severe augmentation, while not common in the first year of treatment, can develop even after years on the medication [28, 29].
Alternative therapy options, such as alpha-2-delta ligands (gabapentin, pregabalin) have shown promising results in treating RLS symptoms [29-31] and are recommended once DA receptor agonist treatment fails [3, 29], but the side effects of the alpha-2-delta ligands often include dizziness, drowsiness, and difficulty concentrating, and there have been case reports of drug-induced depression [32, 33]. While opioids can also be effective in treating RLS, their usage remains problematic due to the inherent possibility of opioid drug abuse and tolerance [34].
Further, duration and intensity of RLS symptoms are similar to those observed in patients with chronic (neuropathic) pain, and the effectiveness of analgesics in treating RLS supports the concept of an overlap between sensory disturbances in RLS and pain modulatory pathways in chronic pain [35, 36]. Similarly to RLS, chronic pain does not resolve on its own and generally requires long-lasting or life-long treatment, often relying on morphine or its derivatives.